Knockdown of PTEN Disrupts PINK1/Parkin-mediated Mitophagy and Promotes Hippocampal Neuronal Cell Death Following Experimental Status Epilepticus

Aberrant mitophagy due to mitochondrial defects via oxidative stress has a strong potential to cause epilepsy. However, PINK1 signaling regarding damaged mitochondria- and oxidative stress-mediated mitophagy during status epilepticus (SE) remains to be fully elucidated. Therefore, the present study aimed to clarify this molecular mechanism in SE animal model. We used pilocarpine-induced SE animal model to investigate the molecular mechanism of SE. Our data exhibited that the hippocampal tissue of rats during SE increased the expression and PTEN and mitophagy-related markers (PINK1, Parkin, p-Drp1 and LC3B-II), showed the mitochondria dysfunction (oxygen consumption and mitochondrial fission), increased the oxidative stress, displayed an mitophage feature (mitophagic vacuole formation), and induced apoptotic cell death. Of note, SE-increased oxidative stress from the hippocampal tissue induced PINK1/Parkin-mediated mitophagy effects via an PTEN-dependent manner. Inhibition of PTEN expression by siRNA transfection in the hippocampal tissue blocked PINK1/Parkin-mediated mitophagy effect caused by oxidative stress. Subsequently, inhibition of PTEN expression enhanced Drp1-mediated mitochondria fission and ensuing damaged mitochondrial-induced apoptotic cell death. In conclusions, these findings reveal that hippocampal neuronal cells during SE display features of oxidative stress, damaged mitochondria, apoptotic cell death and mitophagy, and PTEN contribute to activate these program in hippocampal neuronal cells.